Binding of epidermal growth factor to epidermal growth factor receptor can activate the activity of tyrosine kinase, and in consequence may activate reactions that lead to cellular proliferation. Overexpression and overactivity of EGFR may cause uncontrollable cell division.
The epidermal growth factor receptor tyrosine kinase (EGFR-TK), the first discovered protein tyrosine kinase, is widely distributed in human tissue cell membranes and overexpresses in most of tumours (e.g. bladder cancer, non-small cell lung cancer, ovarian cancer, breast cancer, stomach cancer, esophageal cancer and so on). There is an adenosine triphosphate (ATP) binding site in EGFR intracellular region. Therefore, EGFR inhibitors may competitively bind to the ATP binding site, and thereby inhibit EGFR phosphorylation, block the downstream signal transduction and in turn inhibits the growth, differentiation and metastasis of tumour cells. Nowadays the targeted tumour therapy based on EGFR receptor as a target is one of active research areas in cancer treatment. In clinical studies it has also achieved remarkable results, in which the research of small molecular compounds based on quinazoline as a nucleus is most prominent.
Some quinazoline compounds, which bear a phenylamino substituent at the 4-position and substituents at the 6- and/or 7-position, are disclosed to have activity to inhibit receptor tyrosine kinase in Patent Application Publication Nos. WO96/33977, WO96/33978, WO96/33979, WO96/33980, WO96/33981, WO97/30034, WO97/30035, WO97/38994, WO98/13354, WO00/55141, WO00/56720, WO02/41882, WO03/82290, EP566226 and EP837063. All the above-mentioned documents are hereby incorporated herein by reference.
4-(2,3-dihalophenylamino)quinazoline compounds substituted by heterocyclyloxy group or heterocycloalkoxy groups at 6-position are disclosed in Patent Application Publication No. WO03/082831. Said compounds are inhibitors of erbB, particularly EGFR tyrosine kinase. The above-mentioned document is hereby incorporated herein by reference.
Small molecular drugs for anti-tumour based on EGFR acceptors and comprising quinazoline as a nucleus, for example, gefitinib (Iressa), erlotinib and lapatinib have been successively approved by FDA for clinical uses. In China Dr. Yinxiang Wang and Dr. Lieming Ding developed an EGFR acceptor inhibitor, icotinib (Conmana), based on erlotinib (Tarceva). The third-period clinical trial showed that icotinib (Conmana) has an efficacy equal to erlotinib and better safety, and its dosage and regimen of administration are more suitable for Chinese. Icotinib was approved to be used for treating advanced non-small cell lung cancer by the Chinese food and Drug Administration in June 2011.
The present invention is based on erlotinib and icotinib. A class of quinazoline compounds containing isoxazole heterocycles has been synthesized, wherein isoxazole heterocycle is introduced into the nucleus of quinazoline. The in vitro activity of inhibiting epidermal growth factor receptor tyrosine kinase (EGFR-TK) of this class of compounds has shown that said compounds have more strong activity of inhibiting EGFR-TK, and can be used as anti-tumour drugs or lead compounds.